2-aroylmethyl-3-oxo-3,4-dihydro - 1,4,2-benzothiazines and their preparation



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2,894,945 Patented July 14, 1959 tie Frederick K. Kirchner, Delmar,N.Y., assignor to Sterling Dl'llg Inc., New York, N. Y., a corporationof Delaware No Drawing. Applicationjune 20, 1956 Serial No. $92,433

in Claims. or. 260-243 This invention relates to processes forthepreparation of substituted-benzothiazines' If is, more particularlyconcerned with the preparation of 2-aroylmethyl-3-oxo-3,4-dihydro-1,4,2-benzothiaZines and the noVelZ-aroylmethyl 3 oxjof 3,4-dihydro 1,4,2 b'enzothiaz'ines produced thereby.

Although relatively few have been reported, methods for preparingbenzothiazines substituted in the 2-position by lower-alkanoyl and aroylradicals are known. Thus 2 benzoyl 3 oxo 3,4 dihydro {1,4,2benzothiazine has been prepared from 2,2f-dianiinodiphenyl disulfide andethylbenzoyl acetate. Other 2-substituted benzothiazines have beenprepared from Z-aminobenzenethiol and cap-unsaturated acids, ketones,and a-halogenated acids. All these methods suffer from severaldisadvantages. The yields are low, mixtures are obtained, the reactionconditions are drastic and the course of the reaction is notpredictable. For example in the case of a,[3-unsaturated acids, thesulfur containing portion of 2-aminobenzenethiol adds to the ethyleniclinkage with the sulphur becoming attached to the fi-carbon atom.

This is followed by ring closure to give seven-membered rings; Thereaction conditions are, very critical as evidenced by the fact thatheptabenzothiazines, benzothiazines or benzothiazoles can resultdependingon the temperature employed in carrying out the reaction. Onlyin the special case of maleic acid is a benzothiazine formed initiallydue to the fact that one of the two carboxyl groups is in a position toreact with the amino group to form a normal six-membered ring.

Hitherto, no compositions having the formula I have been reported.Therefore, it is the principal object'of this invention to provide amethod for preparing 2-aroylmethyl 3 x0 3,4 dihydro 1,4,2 benzothiazinesin a predictable manner and in good yields.

A further object of the invention is to provide a method for preparing2-aroylmethyl-3-oxo-3,4dihydro-l,4,2-benzothiazines which involves lowertemperatures and shortened reaction times than the methods-now known forthe preparation of the-benzothiazine ring system.

Still another object of the invention is to provide new compounds havinga surprisingly high activity as antifungal agents. I

I have now found that Z-aminobenzenethiol adds to a fl-aroylacrylic acidin'such a way that the sulfur-containing portion of the molecule addsthe carbon atom beta to the carbonyl group and'alpha to the carboxylgroup. This is followcd'by the removal of water between the carboxylgroup and the amino group to form aZ-aroylmethyl-3-oxo-3,4-dihydro-1,4,2-benzothiazine.

The present invention provides a method of preparing new and usefulcompounds in which the'3 oxo-3,4-dihy dro-l,4,2-benzothiazine nucleus isattached through the 2-position by a methylene bridge to 'the carbonylcarbon of an aroyl radical. v

The present invention affords new compounds having the formula zsnongoomwherein Ar is an arylradical of the benzene series. A preferred group ofaryl radicals consists of the unsubstituted phenyl radical and phenylradicals substituted by from one to three radicals selected from thegroup consisting of alkyl, lower-alkoxy, lower-alkylmercapto,loweralkylsulfonyl, amino, lower-acylamino, nitro, halogen and hydroxy.These substituents can be in any of the available positions of thephenyl nucleus, and where more than one, can be the same or differentand can be in any of the various position combinations relative to eachother. The lower-alkoxy, lower-alkylmercapto, loweralkylsulfonyl andlower-acylamino substituents have preferably one to six carbon atoms,including such substituents as: methoxy, ethoxy, n-propoxy, isopropoxy,isobutoxy, n-pentoxy, n-hexoxy and the like for loweralkoxy;methylmercapto, ethylmercapto, n-propylmercapto, isobutylrnercapto,n-hexylmercapto, and the like for lower-alkylmercapto; methylsulfonyl,ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl,npentylsulfonyl, isohexylsulfonyl and the like for loweralkylsulfonyl;and acetylamino, propionylamino, isopropionylamino, butyrylamino,isobutyrylamino, valerylamino, caproylamino and the like forlower'acylamino. The alkyl substituents have preferably from one totwelve carbon atoms, including such substituents as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,isoheptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Thehalogen atom can be any of the halogens fluorine, chlorine, bromine oriodine.

Of the compounds prepared by the process of the invention, those havingantifungal activity are of particular value. Included in this preferredaspect are compounds of Formula 1 above in which Ar is aphenyl radicalsubstituted byfrom one to three radicals selected from the groupconsisting ofalkyl, lower-'alkoxy, lower-alkylmercapto,lower-alkylsulfonyl, amino, ,lower-acylamino, nitro, halogen and hydroxyand where the groups have the meanings given above.

The compounds of Formula I above in which Ar is a phenyl radicalsubstituted by from one to three halogen atoms have high antifungalactivity in vitro against genera such as Tricophyton and Aspe'rgillusand as such constitute an especially preferred class.

s The process of the invention is'carried out by reacting a,B-benzoylacrylic acid with about a one molar equivalent ofZ-aminobenzenethiol at a temperature between about 25 C. and 150 C. Thereaction is preferably carried out in a solvent inert under theconditions of the reaction. Such solvents include aromatic'hydrocarbonse.g. benzene; toluene, xylene etc.; aliphatic hydrocarbons such ashexane, heptane, octane etc.; chlorinated hydrocarbons such as methylenedichloride, chloroform, carbon tetrachloride etc.; and others such asdiethyl ether, di-n-butyl ether, tetrahydrofuran etc.

The reaction proceeds at room temperature in'diethyl ether but the bestmode for carrying out the process comprises adding Z-aminobenzenethiolto a benzene, toluene or xylene solution of apfl-benzoflacrylic acid at50- C.' Under these conditions, the'reaction is immediate and the2-aroylmethyl-3-oxo-3,4-dihydro-l,4,2-benzothiazine isrecovered bycooling the reaction mixture. Although the reaction can be carried outin the presence of water, it is preferred to conduct the reaction byheating the reactants in a steam-volatile, water-immiscible solventwhile removing the water formed by azeotropic distillation. Theseparation of water commences as soon as the addition ofZ-aminobenzenethiol is begun and ceases when the addition is complete.The reaction is essentially complete at this stage but the reactionmixture can be refluxed to insure complete reaction.

In a modification of the process of the invention a method is providedfor preparing compounds having the Formula II CHGHzCOAr wherein Ar hasthe meaning given above and X is a halogen atom. The halogen atom can beany of the halogens, fluorine, chlorine, bromine and iodine.

The process is carried out by condensing a4-halogensubstituted-2-nitrothiophenol with the appropriatefi-benzoylacrylic acid and reducing the resultant product with an agenteffective to reduce a nitro to an amino group. The intermediate 2-(4-halo-3 -nitrophenylmercapto -3- (aroyl)propionic acid can be isolatedand characterized although it is preferred to carry out the reaction inone step Without the isolation of any intermediates. Although I preferto use zinc and acetic acid as the reducing agent, this is not acritical step and numerous reducing agents effective in reducing nitroto amino groups can be used.

Thus, the processes for preparing compounds of Formulas I and II proceedin essentially the same manner .e.g., the sulfur containing residue addsacross the double bond of a B-benzoylacrylic acid and ring closure tothe desired compounds follows. In the process for preparing compounds ofFormula II it is, of course, necessary to reduce the nitro group to anamino group before ring closure is effected.

The intermediate 4-halo-2-nitrothiophenols are a known class ofcompounds. They can be prepared by reacting a 2,5-dihalonitrobenzenewith sodium :sulfide.

The intermediate fl-benzoylacrylic acids are a known class of compounds.They can be prepared by reacting maleic anhydride with the appropriatesubstituted benzene in the presence of aluminum chloride.

The following examples will further illustrate the invention, withouthowever limiting the same thereto.

EXAMPLE 1 Z-phenacyl-3-ox0-3,4-dihydr0-1 ,4,2-benz0thiazine In a 1 literthree-necked flask fitted with a Dean-Stark water separator and droppingfunnel was placed 37 grams of .13-benzoylacrylic acid in 200 m1. of drytoluene. The mixture was heated to dissolve the fl-benzoylacrylic acidand heating was continued until reflux commenced. To the refluxingsolution was addeddropwise 25 grams of 2- amlnobenzenethiol in 10.0 ml.of dry toluene. The reaction was instantaneous as evidenced by theimmediate 1 accumulation of water in the Dean-Stark trap. The separationof water ceased after the addition of the toluene solution ofZ-aminobcnzenethiol. The solution was refluxed for one hour then pouredinto an Erlenmeyer flask and cooled. The crystals which separated werecollected .by suction filtration, washed with toluene andSkellysolve C.After recrystallization from toluene there was obtained 45 grams of.2-phenacyl-3-oxo-3,4-dihydro-1,4,2- benzothiazine, M.P. 172.9-175.0 0.(corn).

Analysis.-Calcd for C H NO S: Nitrogen 4.94; ,sulfur 11.32. Found:Nitrogen 4.94; sulfur 10.95.

2 phenacyl 3 oxo 3,4 dihydro r 1, 6 2 thiazlne oxime was prepared from2-phenacyl 3 9 3,4 dihydro 1,4,2 benzottttaziueesd hydroxylhydrochloride. The 2-phenacyl 3 oxo 3.,4 dihydro- 1,4,2 benzothiazineoxime thus obtained had the M.P. 196-2010 C. (corn).

Analysis.-Calcd for C H N O S: Nitrogen 9.39; sulfur 10.74. Found:Nitrogen 9.04; sulfur 10.51.

When mixed with benzenesulfonyl chloride, Z-phenacyl 3 oxo 3,4 dihydro1,4,2 benzothiazine oxime underwent a Beckman rearrangement to give2-phenylcarbamylmethyl 3 oxo 3,4 dihydro 1,4,2 benzothiazine, a compounddisclosed and claimed, and whose structure is proved in my co-pendingapplication, Serial No. 592,489, filed June 20, 1956.

Thus, that the structure of the 2-aroylmethyl-3-oxo-3,4-dihydro-1,4,2-benzothiazines is as shown follows from theabove-mentioned structure proof and chemical analy- SIS.

EXAMPLE 2 2 (4 n dodecylphenacyl) 3 oxo 3,4 dihydro-'1,4,2-benzothiazine was prepared from 55 grams of [3-(4-n-dodecylbenzoyl)acrylic acid and 20 grams of 2- aminobenzenethiol in175 ml. of dry toluene according to the procedure described in Example'1. The 2-(4-ndodecylphenacyl) 3 oxo 3,4 dihydro 1,4,2 benzothiazinethus obtained weighed .61 grams and had the M.P. 118120.4 C. (corn).

Analysis.Calcd for C I-I NO S: Nitrogen 3.10; sulfur 7.10. Found:Nitrogen 3.14; sulfur 6.79.

EXAMPLE 3 2 (4 n octylphenacyl) 3 oxo 3,4 dihydro- 1,4,2-benzothiazinewas prepared from 35 grams of (4-n-octylbenzoyl)acrylic acid and 15.5grams of 2- aminobenzenethiol in 150 ml. of dry toluene according to theprocedure described in Example 1. The 2-(4-noctylphenacyl) 3 0x0 3,4dihydro 1,4,2 benzothiazine thus obtained had the M.P. 117.2118.7" C.(corn) andweighed 29.5 grams.

Analysis.-Calcd for C H NO S': Nitrogen 3.54; sulfur 8.11. Found:Nitrogen 3.57; sulfur 7.99.

2 (4 n octylphenacyl) 3 oxo 3,4 dihydro- 1,4,2-benzothiazine was foundto possess antifungal activity in vitro as follows:

Maximum Effective Dilution Organism 4 V Funglstatlc Funglcldal '1".interdigitale 1:133, 000 1:133, 000 T. mentagrophytes. -1:133,0001:133,000 As. ,m'ger 1:100, 000 1:100, 000 T. gypseum 1:100, 000 1:100,000 Momlia albictms 1:100, 000 1:100, 000

EXAMPLE 4 2-(4-n-butylphenacyl)-3-oxo-3,4-dihydro- 1,4,2 benzothiazinewas prepared from 17.5 grams of fl-(4-n-butylbenzoyDacrylic acid and 10grams of 2-.aminobenzenethiol in ml. of dry toluene according to theprocedure described in Example 1. The 15 grams of2-(4-n-butylphenacyl)-3-oxo-3,4-dihydro-1,4,2-benzothiazine thusobtained had the M.P. 13l.l-13 l.8 C. (corn).

Analysis.Calcd for C H NO S: Nitrogen 4.13; sulfur 9.44. Found: Nitrogen4.20; sulfur 9.08.

EXAMPLE 5 an exothermic reaction took place.

- EXAMPLEG- v 2-(4-methylphenacyl) 3-oxo-3,4-dihydro-1,'4,2 ben--zothiazine was prepared from 27.8 grams of ,B-i(4-meth-yl'benzoyl)acrylic acid and 18.5 grams of Z-amindbenzenethiol in 130ml. of dry toluene according to the procedure described in Example 1.The 33.7 grams of 2-(4- vmethylphenacyl) 3-oxo 3,4-dihydro 1,4,2benzothiazine thus obtained had the M.P. 204.8-206.3 C. (corn).

Analysis.--Calcd for C I-1 N0 8: Nitrogen 4.71; sulfur 10.78. Found:Nitrogen 4.78; sulfur 11.20.

EXAMPLE 7 2-(4-methoxyphenacyl) 3-oxo-3,4-dihydro-1,4,2 ben- -zothiazinewas prepared from 19 grams of fl-(4-methoxyb'enzoyl-)acry1ic acid and 12grams of Z-aminobenzenethiol in 150 ml. of dry'toluene according to theprocedure described in Example 1. The 29 grams of2-(4-methoxyphenacyl)3-oxo-3,4-dihydro-1,4,2-benzothiazine thus obtainedhad the M.P. 1944-1962"- C. (corn).

Analysis.Calcd for C H NO S: Nitrogen 4.47; sulfur 10.23. Found:Nitrogen 4.55; sulfur 10.01.

EXAMPLE 8 2-(4-ch lorophenacyl)-3-oxo-3,4-dihydro-1,4,2-benzothiiazinewas prepared from 21 grams of fi-(4-chlorobenzoyl) acrylic acid and 14grams of Z-aminobenzenethiol in 200 ml. of dry toluene according to theprocedure described in Example 1. The 24.3 grams of 2(4-chlorophenacyl)-3- 'oxo-3,4-dihydro-1,4,2-benzothiazine thus obtainedhad the M.P. 193.1-195.2 C. (corn).

Analysis.Calcd for C H' ClNO S: Chlorine 11.16; sulfur 10.09. Found:Chlorine 10.85; sulfur 10.29.

2-(4-chlorophenacyl -3-oxo-3 ,4-dihydro-1,4,2-benzothiazine was found topossess antifungal activity in vitro as A'susp'ension of 19 grams of4,4'-dichloro-2-2'-dinitrodiphenyldislflrfide was mixed with a solutionof 7.0 grams of sodium sulfide nonahydrate and 3 grams of sodiumhydroxide in 25 ml. ofwater. The mixture was heated for fifteen minutesthen 50 ml. of water added. The hot solution was filtered and the hotfiltrate diluted with water and acidified with dilute hydrochloric acid.T be solid 2- nitro-4-ch1orothiophenolwhich separated was collected bysuction filtration,'washed with water and pressed dry. This compound wasused without further purification in the following preparation.

The 2-ni tro-4-chlorothiophenol obtained as described above was added toa hot solution of p-benzoylacrylic acid in 600 ml. of glacial aceticacid and the mixture heated until. solution was complete. To the warmsolution was 'added in small quantities, 30 grams of zinc dust. Heatingwas discontinued while the zinc was being added since After the additionwas complete 2-00 ml. of glacial acetic acid was added and r thesuspension .h'eatedto reflux then filtered while hot to remove unrcacted'zinc. Cooling of the filtrate caused the separation of a white solidwhich was collected by suction filtration. Recrystallization fromtoluene gave 6 6 grams of 2-phenacyl-3-oxo- 6-chloro 3,4-dihydro-1,4,2-benzothiazine, M.P. 215-219 C. (corn).

Analysis.Calcd for C H CINO S: Nitrogen 4.41; sulfur 10.09. Found:Nitrogen 4.31; sulfur 10.22.

. Using the manipulative procedure described above 2-(4-n-octylphenacyl)-3-oxo-6-bromo-3,4-dihydro-1,4,2 benz othiazine can beprepared by reacting )9(4-n-octylbenzoy1)acrylic acid with 2nitro-4-bromothiophenol; 2-(2,4- dichlorophenacyl)3-oxo-6-iodo-3,4-dihydro-1,4,2 benzothiazine can be prepared by reacting,B'(2,4-dichlorobenzoyl)acrylic acid with 4,4-diiodo-2,2dinitrodiphenyldisulfide which can be prepared by nucleophilicdisplacement of the chlorine atom of 2-chloro-5-iodonitrobenzene withsodium sulfide;2-phenacyl-3-oxo-6-fiuoro-3,4-dihydro-1,4,2-benz0thiazine can beprepared by reacting [3- benzoylacrylic acid withZ-mercapto-S-fluoronitrobenzene which can be prepared by nucleophilicdisplacement of the 2-fiuorine atom of 2,5-difiuoronitrobenzene withsodium sulfide; and 2-(2,4,6-trimethylphenacyl)-3-oxo-6-chloro-3,4-dihydro-1,4,2-benzothiazine can be prepared by reactingfl-(2,4,6-trimethylbenzoyl)acrylic acid with 2-nitro-4-chlorothiophenol.

EXAMPLE 10 2-(3,4-dichlorophenacyl)-3-oxo-3,4-dihydro-1,4,2benzothiazine was prepared from 15 grams of3-(3,-4-dichlorobenzoyl)acrylic acid and 8.2 grams ofZ-aminobenzenethiol in 175 ml. of dry toluene according to the proceduredescribed in Example 1. There was thus obtained 12 grams of2-(3,4-dichlorophenacyD-3-oxo-3,4-dihydro l, 4,2-'benzothiazine, M.P.192.3'194.0 C. '(corr.).

Analy'sis.-Calcd for C l-I Cl NO S: Nitrogen 3.98; chlorine 20.13.Found: Nitrogen 4.14; chlorine 20.05.

' 2-(3,4-dichlorophenacyl)-3-oxo-3,4-dihydro-1,4,2 benzothiazine wasfound to possess antifungal activity in vitro as follows: I

Maximum Efiective Dilution Organism Fungistatic T. interdz'gitale M.albicans EXAMPLE 11 2-(3-nitrophenacyl) -3-oxo-3,4-dihydro-1,4,2benzothiazine was prepared from 6.5 grams of fl-(3-nitrobenzoyl) acrylicacid and 5 grams of 2-aminobenzenethiol in ml. of dry benzene accordingto the procedure described in Example 1. The 5.5 grams of2-(3-nitrophenacyl)-3 -oxo-3,4-dihydro-1,4,2-benzothiazine thus obtainedhad the M.P. 1905-1937 C. (com).-

Analysis.-Calcd for C H N O S: Nitrogen 4.26;

' sulfur 9.76. Found: Nitrogen 4.26; sulfur 9.64.

2-(3-nitrophenacyl) -3-oxo-3,4-dihydro-1,4,2' benzothiazine was found topossess antifungal activity in vitro as follows: 1

EXAMPLE 12 2-nitro-4' chlorothiophenol, obtained as described in etherand dried at 75 C. A portion of theadduct thus obtained was used withoutfurther purification as de scribed below. Recrystallization ofanotherportion from methyl Cellosolve gave yellow crystals of2-(4-ch1oro-2- nitrophenylmercapto) -3-( 4fluorobenzoyl propionic acid,

, MP. 207208 C. (dec.) (corn).

Analysis.-Calcd for C H ClFNO S: Nitrogen 3.65; sulfur 8.35. Found:Nitrogen 3.60, sulfur 8.29.

2-(4-fluorophenacyl)-3-0x06-chl0ro-3,4-

' dihydrod,4,2-benz0thiazine The crude2-(4-chloro-2-nitrophenylmercapto)3-(4- fluorobenzoynpropionic. acidobtained above was dissolved in 400 ml. of boiling glacial acetic acidand grams of zinc dust added in small portions. The mixture wasrefluxedfor thirty minutes, during which time the supernatant liquidbecame nearly colorless. I Then the liquid was filtered by suction andthen run in a thin stream into three liters of water causing theseparation of an oil-white precipitate which was collected by suctionfiltration. The solid was taken up in boiling glacial acetic acid, thesolution treated with decolorizing charcoal and filtered. The hotfiltrate was diluted with 50 ml. of water and allowed to cool. The solidproduct which separated was collected by suction filtration, washed withabsolute ether and dried at 75 C. The 7 grams of 2-(4-fiuorophenacyl -3oxo-6-chloro-3,4-dihydro-1,4,2-benzothiazine thus obtained had the M.P..243-24S C. (corn).

Analysis.-Calcd for'C H ClFNO S: Nitrogen 4.17; sulfur 9.55. Found:Nitrogen 3.97; sulfur 9.37.

Z-benzothiazine was found-to possess antifungal activity According tothe manipulative procedures described above 2-,(4-chlorophenacyl)3-oxo-6-fiuoro-3 ,4 dihydro- 1,4,2-benzothiazine can be prepared byreducing 2-(4- fluoro-Z-nitrophenylmereapto)-3-(4chlorobenzoyl)propionic acid with zinc; the intermediate 2-(4-fluoro-2-nitrophenylmercapto ).-3-(4 chlorobenzoyl)propionic acid can .beprepared by reacting 2-nitro-4-fluorothiophenol, prepared by reacting2-chloro-5-fluoronitrobenzene with sodium sulfide, withfi-(4-chlorobenzoyl)acrylic acid; 2- (3,4-dichlorophenaoyl)-3-oxo 6bromo 3,4 dihydro- 1,4,2-benzothiazine can be prepared by reducing 2-(4-bromopheny1mercapto)-3 (3,4 dichlorobenzoyl)propionic acid, preparedfrom. 2-nitro-4-chlorothiophenol and ,8-(3,4-dichlorobenzoyl)acrylicacid, with zinc; and 2-(4- methoxyphenacyl) 3 oxo 6 iodo3,4-dihydro-1,4,2- benzothiazine can be prepared by reducing2-(4-iodo-2- nitrophenylmercapto)-3 (4 methoxybenzoyl)propionic acid,prepared by reacting 2,5-diiodonitrobenzene with sodium sulfide followedby condensation with fl-(4-rnethoxybenzoyl)acrylic acid, with zinc.

EXAMPLE 13 z- (4 aceta .idqp nacy )-3 ox0 d hy r benzothiazine wasprepared from 13 grams of fl-(4-acetamidobenzoyDacryIic acid and 7.5grams of Z-aminobenzenethiol in ml. of dry toluene according to theprocedure .describedinExample 1. The 2-(4- acetamido- 'phenacyl) 3-oxo-3 ,4-dihydro- 1 ,4,2-benzothiazine thus obtained weighed '12 gramsand had the M.P. 236.3237.7 C. (corn).

Analysis..Calcd for C H N O S: Nitrogen 8.23; sulfur 9.42. Found:Nitrogen 8.33; sulfur 9.54.

EXAMPLE '14 2- (4 -am inophenacyl -3-oxo-3,4-diizydr0-1,4,2-

. .bgnzothiazine A suspension of 16.5 grams of2-(4-acetamidophenacyl)-3-oxo-3,4:dihydro-1,4,2 .-'benzothiazine(Example 13) in 500 ml. of absolute ethyl alcohol and 100 ml. of

concentrated hydrochloric acid was refiuxedfor two hours I then leftstanding over night. The crystals thus obtained were removed by suctionfiltration and suspended in 400 ml. of hot 95% ethyl alcohol. The hotsolution was filtered, the filtrate diluted with 10 ml. of concentratedammonium hydroxide and 400 m1. of water and the solution cooled in anice bath. The'solid material thus obtained was removed by suctionfiltration and dried at 75 C. togive 6.7grams of2-(4'arninophenacyl)-3-oxo-3,4-

di'nydro-l,4,2-benz0thiazine M.P. 1938-1960" C. (corn).

Analysis.-Calcd for C H N O S: Nitrogen 9.36; sulfur 10.71. Found:Nitrogen 9.53; sulfur 11.15.

2-(4-aminophenacyl)-3-oxo3,4 dihydro 1,4,2-benzothiazine was found topossess antifungal activity in vitro EXAMPLE 15 2-(4-butyramidophenacyl)-3-oxo-.i,4-dihydro- 1,4,2-benz0thiazine A mixture of 4 grams of2-(4-aminophenacyl)-3-oxo- 3,4-dihydro-l,4,2-benzothiazine (Example'14), 3 grams of butyric anhydride and 20 ml. of pyridine was heated ona steam bath for 30 minutes. Addition of ice and water to the solutioncaused the separation of an oil that quickly solidified. The solid wascollected by suction filtration, washed well with water then taken up inacetone. The acetone solution was filtered and the filtrate concentratedby the removal of acetone. The concentrate was taken up in water andagain concentrated to yield 4 grams of2-(4-butyramidophenacyl)-3-oxo-3,4- dihydro-l,4,2-benzothiazine M.P.218.0219.7 C. (corn).

Analysis.-Calcd for C H N O sz Nitrogen 7.61; sulfur 8.70. Found:Nitrogen 7.51; sulfur 8.86.

EXAMPLE 16 2-(4-hexanamidophenacyl)-3-0xo-3,4 dihydro 1,4,2-benzothiazine was prepared from 6 grams of 2-(4-aminophenacyl) -3 -oxo-3,4-dihydro-1,4,2-benzothiazine (Example 14), 4.5 grams of caproicanhydride and 20ml. of dry pyridine according to the procedure describedin Example 13. There was thus obtained 6.5 grams of 2-(4-hexanamidiphenacyl)-3-oxo-3,4-dihydro 1,4,2 benzothiazine, M.P. -1854 C.(corn).

Analysis.--Calcd for C H N O S: Nitrogen 7.07; sulfur 8.08. Found:Nitrogen 7.31; sulfur 8.12.

EXAMPLE 17 2(4-fluorophenacyl)-3-oxo-3,4-dihydro 1,4,2 "benzethiazinewas prepared from 9.7 grams of B-(4-fluorobenzoyl) acrylic acid,prepared from 225' grams of fluoro benzene and 229 grams of maleicanhydride, M.P. 135 .5- 136.7 C. (corn), and 7 grams ofZ-aminobenzenethiol in 100 ml. of dry toluene according to the proceduredescribed in Example 1." There was thus obtained grams of2-(4-fluorophenacyl)-3-oxo-3,4-dihydro-1,4,2- benzothiazineMP. 1'71.11'7 3.4f C. (corn). Analysis-.Caled for C I-I FNO S: Nitrogen 4.65; sulfur10. 64. Found: Nitrogen 4.57; sulfur 11.07. i '2-(4-fluorophenacyl)-3-oxo,-3, 4 dihydro 1,4,2-benzo- {hiazine was found to possessantifungal activity as folows:- r

Maximum Effective Dilution Organism Fungistatic Funglcidal T.interdigitale 1=1o0,u00 1:66, 000 T. I ophyt -1:100,000' 1Z50,0U0 v1266,000 I:50,000 12190, 000 1:50, 000 1:100,000 12100,000

EXAMPLE 18 '2-(2,4-dichlorophenacyl)-3 oxo 3,4 dihydro 1,4,2-benzothiazinewas prepared from 10 grams of (342,4- dichlorobenzo-yl)acrylic acid and 5.2 grams of Z-aminobenzenethiol :in 150 ml. of drytoluene according to the proceduredescribed in Example 1. There was thusobtained -10 grams of 2-(2,4-dichlorophenacyl)-3-oxo-3,4-

-dihydro- 1,4,2-benzothiazine M.P. 185.6190.0 C. (corn).

.A na lysis.Calcd for C H Cl NO S: Nitrogen 3.98; chlorine 20.13. Found:Nitrogen 3.90; chlorine 20.25.

2'- 2,4-dich1orophenacyl) -3 oxo v 3,4 dihydro 1,4,2- benzothiazine wasfound to possess antifungalactivity as follows:

Maximum Effective I v Dilution Organism m Fungistatic Fungicidal T.interdigitale 1:133, 000 1:133, 000 T. mentagroph' tes 1:133, 000 1:100,000 As. m'ger 1:100,000 T. gypseum 1:133,000 1:133, 000 v 1 1'100,0001:100,000

EXAMPLE 19 2-(2,4dihydroxyphenacyl)-3-oxo-3,4 dihydro 1,4,2-benzothiazine was prepared from 17 grams of [3-(2,4-dihydrox'ybenzoynacrylic acid and 10.5 grams of 2- aminobenzenethiol in200 ml. of dry toluene according to the procedure described inExample 1. The 2-(2,4-dihydroxyphenacyl)-3-oxo-3,4-dihydro 1,4,2benzothiazine thus obtained weighed 12 grams and had the M.P.253.4-256.4 C. (corn).

Analysis.-Calcd for C H NO S: Nitrogen 4.44; sulfur 10.17. Found:Nitrogen 4.37; sulfur 10.14.

EXAMPLE 20 aminobenzenethiol; 2 2 hexylsulfonylphenacyl)r3-oxo-3,4-dihydro-1,4,2-benzothiazine can be prepared by oxidizing3-(2-hexylmercaptobenzoyl)acrylic acid and reacting the resultingp-(4-hexylsulfonylbenzoyl) acrylic acid with Z-aminobenzenethiol; and2-(4-isobutylsu1fonylphenacyl)-3-oxo-3,4-dihydro-1,4,2-benzothiazine canbe prepared by oxidizing p-(4-isobutylmercaptobenzoyl) acrylic acid andreacting the resulting fi-(4-isobutylsulfonylbenzoyl)acrylic acid withZ-aminobenzenethiol.

According to the manipulative procedures described in the above examples2-(2-hydroxy-4-methy1-5-chlorophenacyl)3-oxo-3,4-dihydro-1,4,2-benzothiazine can be prepared by reacting'fi-(Z-hydroxy-4-methyl5-chlorobenzoyl)acrylic acid with2-aminobenzenethiol; 2-(4- bromophenacyl) -3-oxo-3,4-dihydro 1,4,2benzothiazine can be prepared by reacting p-(4-bromobenzoyl) acrylicacid with Z-aminobenzenethiol; 2-(2,5-dimethylphenacyl)-3-oxo-3,4-dihydro-1,4,2-benzothiazine can be prepared by reactingfi-(LS-dimethylbenzoyl)acrylic acid with 2- aminobenzenethiol;2-(4-hexoxyphenacyl) -3-oxo-3 ,4 dihydro-1,4,2-benzothiazine can beprepared by reacting fl-(4-hexoxybenzoyl)acrylic acid withZ-arninobenzenethiol;2-(4-iodophenacyl)3-oxo-3,4-dihydro-1,4,2-benzothiazine can be preparedby reacting 13-(4-iodobenzoyl)- acrylic acid with 2-aminobenzenethiol;2-(4-hexylmercaptophenacyl)-3-oxo-3,4 dihydro 1,4,2 benzothiazine can beprepared by reacting 13-(4-hexylmercaptobenzoyl)- acrylic acid withZ-aminobenzenethiol, the intermediate,8-(4-hexyl-mercaptobenzoyl)acrylic acid can be prepared by reactinghexylmercaptobenzene with maleic anhydride; 2 (3nitro-4-bromophenacy1)-3-oxo-3,4-dihydro- 1,4,2-benzothiazine. can beprepared by reactingfi-(B- nitro- 4-bromobenzoyl) acrylic acid with2-arninobenzenethiol; and 2-(2-hydroxy-3,S-dibromopheriacyl)-3-oxo-3,4-dihydro-1,4,2-benzothiazine can be prepared by reacting,8-(2-hydroxy-3,5:dibromobenzoyl)acrylic acid with 2- aminobenzenethiol.

, The 2-aroy1methyl-3-oxo-3,4-dihydro 1,4,2-benzothiazines were found tohave fungicidal and fungistatic activity when tested in conventionalserial dilution tests against various fungi, for example, T richophytoninterdigitale, Trichophyton mentagrophytes, Trichophyton 'gypseum, Aspergillus nigr and 'Monilia albicans.

They are preferably employed topically; and they can be compounded'withconventional excipients and used in the form of a powder, a liquid, anointment, a salve, or any other vehicular form suitable foradministeringantifungal agents. My benzothiazines can be formulated inthese various vehicular forms in dilutions of about 121000 to about1:100,000.

I claim:

1. A process for preparing a compound having the formula which comprisesheating [i-(SA-dichlorobenzoyl)acrylic acid with Z-aminobenzenethiol inan inert solvent at a temperature between about 50 C. to C.

2. A process for preparing a compound having the formula which comprisesheating fi-(4-chlorobenzoyl)acrylic acid with 2-arninobenzenethiol in aninert solvent at a temperature between about 50 C. to 125 C.

3. A process for preparing a compound having the formula nterim -F Hwhich comprises heating fi-(4fluor ob enzoyl) acrylic acid with2-aminobenzenethiol in an inert solvent at a ternperature between about50 C. to 125 C.

4. A process for preparing a compound having the formula scrrct-hco-om(cm)tcm which comprises heating B-(4-n-octylbenzoyl)acrylicacid with Z-aminobenzenethiol in an inert solvent at a temperaturebetween about 50 C. to 125 C.

5. A process 'for preparing ,2-(4-fiuorophenacyl)-3-oxo-6-chloro-3,4dihydro-l,4,2-benzothiazine having the for- .mula

4,2-benzothiazine.

11. A process for preparing 2-aroylmethyl-3-oxo-3,4-dihydro-l,4,2-benzothiazine wherein the aryl portion of the aroylradical is a phenyl radical having from .one to three substituentsselected from the group consisting of alkyl,lower-,alkoxy,;lower1alkylmercapto, lower-.alkylsulfonyl, amino,ilower-acylarnino, nitro, hydroxyv and halogen, whichcomprises heating afi-benzoylacrylicacid with Z-aminobenzenethiol in an inertwsolvent at atemperature between about C. to C.

12. A process for preparing -2-aroylrnethyl-3-oxo-3,4-dihydro-l,4,2-benzothiazine wherein the aryl portion of the aroylradical is dihalogen-substituted phenyl which comprises heating adihalogen-substituted B-benzoylacrylic acid with Z-arninobenzenethiol inan inert solvent at a temperature between about 50 C. to 125 C.

13. A process for preparing 2-aroylmethyl-3- oxo-3 4-dihydro-6X-1,4,2-benzothiazine wherein the aryl portion of the aroylradical is .a benzene radical and X is a halogen atom which comprisesheating a fl-benzoylacrylie acid with a 4-halo-2-nitro-thiophenol ,inacetic acid at a temperature between about 50 C. and 125 C. and reactingthe resulting 2-;(4-halo-2-nitrophenylmercapto)- 3-(aroyl)propionic acidwith a reducing agent effective toreduce nitro groups to amino groupsand isolating the 2-aroylmethyl-3-oxo-3,4-dihydro-6X-*1,4,2benzothiazine thus produced.

14. 2-aroylmethyl-3foxo-3,4-dihydro6X1,4,2 benzothiazine wherein thearyl portion of the aroyl radical is a phenyl radical substituted byfrom one to three substituents selected from the group consisting ofhigher alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkylsulfonyl,amino, lower-acylaminq, nitro, hydroxy and halogen and X is selectedfrom the group consisting of hydrogen and halogen atoms.

15. 2-aroylmethyl-3-oxo-3,4-dihydro 1,4,2 benzothiazine wherein the arylportion of the aroyl radical is dihalogen-substi-tuted phenyl.

16. 2-aroylmethyl-3-oxo-3,4-dihydro 1,4,2 benzothiazine wherein the arylportion of the aroyl radical is higher-alkyl-substituted phenyl.

References Cited in the file of this patent Mills et al.: J. Chem. 'Soc.(1927), p p. 2738 to 2753. Rogers et al.: J. Chem. Soc., 1947 (part 3),pp. 1619 to 1621.

UNITED STATES PATENT OFFICE CERTIFICATE GP (IQRECTION Patent N002,894,946 July 14 i959 Frederick Kc. Kirchner It is hereby certifiedthat error appears in the -printed specification of the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 1, line 62, for "adds the" read adds to the column 3, line 26,for "2-(4- -halo 3 nitrophenylmercapto)3w read 2=- 4=-halo-=2nitrOphenylmercapto 3= column 5, line 18, for "29 grams" read 20 gramsSigned and sealed this 23rd day of February 1960.

(SEAL) Attest:

KARL H AXLINE Attesting Officer ROBERT C. WATSON Commissioner of PatentsUNITED STATES PATENT OFFICE CERTIFICATE GP (IQRECTION Patent N002,894,946 July 14 i959 Frederick Kc. Kirchner It is hereby certifiedthat error appears in the -printed specification of the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 1, line 62, for "adds the" read adds to the column 3, line 26,for "2-(4- -halo 3 nitrophenylmercapto)3w read 2=- 4=-halo-=2nitrOphenylmercapto 3= column 5, line 18, for "29 grams" read 20 gramsSigned and sealed this 23rd day of February 1960.

(SEAL) Attest:

KARL H AXLINE Attesting Officer ROBERT C. WATSON Commissioner of PatentsUNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Noo2,894,946 l4,

Frederick KO Kirchner It is hereby certified that error appears inthe-printed specification of the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

Column 1, line 62, for 'adds the read m adds to the column 3, line 26,for "2%4 halo-=3 nitrophenylmercapto)-3- read 2=-(4=-halo=2-=nitr0phenylmercapto -3== column 5, line 18, for "29 grams" read 20 gramsSigned and sealed this 23rd day of February 1960.

(SEAL) Attest:

KARL AXLINE ROBERT c. WATSON Attesting Officer Commissioner of Patents

11. A PROCESS FOR PREAPRING2-AROYLMETHYL-3-OXO-3,4DIHYDRO-1,4,2-BENZOTHIAZINE WHEREIN THE ARYLPORTION OF THE AROYL RADICALS IS A PHENYL RADICAL HAVING FROM ONE TOTHREE SUBSTITUENTS SELECTED FROM THE GROUP NCONSISTING OF ALKYL,LOWER-SLKOXY, LOWER-ALKYLMERCAPTO, LOWER-ALKYLSULFONYL, AMINO,LOWER-ACYLAMINO, NITRO, HYDROXY AND HALOGEN, WHICH COMPRISES HEATING AP-BENEZOYLACRYLIC ACID WITH 2-AMINOBENEZENTHIOL IN AN INERT SOLVENT AT ATEMPERATURE BETWEEN ABOUT 5/* C. TO 125* C. 14.2-AROYLMETHYL-3-/X/-3,4-DIHYDRO-6X-1,4,2 - BENZOTHIAZINE WHEREIN THEARYL PORTION OF THE ARROYL RADICAL IS A PHENYL RADICAL SUBSTITUTED BYFROM ONE TO THREE SUBSISTUENTS SELECTED FROM THE GROUP CONSISTING OFHIGHER ALKYL, LOWER-ALKOXY, LOWER-ALKYLMERCAPTO, LOWER-ALKYLSULFONYL,AMINO, LOWER-ACLAMINO, NITRO, HYDROXY AND HALOGEN AND IS SELECTED FROMTHE GROUP CONSISTING OF HYDROGEN AND HALOGEN ATOMS.